Syringes

ABSTRACT

A two-part syringe comprises two chambers ( 2,4 ) each chamber having an associated plunger ( 6,8 ) operable to eject fluid therefrom. The plungers ( 6,8 ) are interlinked so as selectively to prevent movement of one of said ( 6,8 ) plungers in its respective chamber ( 2,4 ) dependent upon the position of the other plunger ( 8,6 ). Such an arrangement allows lyophilised drugs to be automatically reconstituted within the syringe prior to injection into a patient.

This invention relates to syringes—particularly, although notexclusively, syringes which are suitable for reconstituting lyophilisedsubstances prior to administration.

Many drugs and medicaments are routinely supplied in lyophilised form.This has the advantage of significantly extending the shelf life of thedrug or medicament, eliminating the need for the drug to be stored undera careful temperature regime or simply permitting storage of a substancewhich would otherwise quickly break down. Immediately prior to beingrequired, the lyophilised drug may be reconstituted by mixing it with asuitable diluent.

Conventionally, lyophilised drugs are supplied in glass vials. Glass isused since it is very inert and may therefore safely be used to store awide variety of substances. Furthermore it has extremely good barrierproperties and therefore permits long term storage without contaminationetc.

A diluent is either extracted from another glass vial by a syringe witha needle for piercing the rubber septum thereof, or is supplied in apre-filled syringe. The diluent is then injected into the vialcontaining the drug by using the needle on the syringe to pierce therubber septum of the drug vial. Once the drug has been reconstituted,the syringe is used to draw the reconstituted drug out of the vial,ready for injection into a patient.

Clearly the requirement to penetrate a relatively small rubber septum atleast once with a needle gives rise to the danger of injury to the user.Furthermore the addition of diluent to the drug is entirely under thecontrol of the user. One problem this can give rise to is that thediluent can be added too quickly. Too high a flow rate of diluent ontothe drug can cause it to shear excessively. Lyophilised drugs tend to bedelicate and some can be damaged by excessive shearing. A high flow ratemay also cause the diluent and drug mixture to undergo undesirablefoaming.

Various arrangement have been proposed for allowing lyophilised drugs tobe reconstituted inside a device thereby avoiding some of the potentialfor injury associated with the conventional method of reconstitution.Examples of such arrangements are shown in WO 01/26718, WO 96/29106 andEP-A-1038543. However, all of the previous arrangements suffer from somedrawbacks.

It is an object of the invention to provide an improved way ofreconstituting drugs and when viewed from a first aspect the inventionprovides a two-part syringe comprising two chambers, each chamber havingan associated plunger operable to eject fluid therefrom, said plungersbeing interlinked so as selectively to prevent movement of one of saidplungers in its respective chamber dependent upon the position of theother plunger.

Thus it will be seen in accordance with the present invention that bysuitable design of the interlinking between the two plungers of atwo-chamber syringe, the order and extent to which each may be operatedcan be controlled. By providing a lyophilised drug and diluentrespectively in the two chambers, for example, such an arrangement couldbe used to ensure that diluent is expelled from its chamber and into thechamber containing the lyophilised drug before the reconstituted drugcan be expelled. Furthermore it can be arranged that the drug cannot beinjected into a patient until the correct quantity of diluent has beenused.

Another possible use for an embodiment of the invention might be toensure that two substances to be administered in conjunction with oneanother are administered in the correct order.

By interlinking the two plungers in accordance with the invention it maybe ensured that, at each stage of a drug preparation and administrationprocedure, only the correct plunger may be actuated. This prevents anypossible accident or misuse of the device meaning that a minimal amountof instruction in how to operate the syringe is required. Thispotentially opens up the possibilities for drugs to be administered bynon-medical staff or by patients themselves, giving increasedconvenience to patients and saving costs.

The two plungers could be interlinked by any suitable means. For exampleone plunger could be arranged to release or set a latch, catch or thelike preventing operation of the other. Preferably, however, a cam meansis associated with the plungers. In a particularly preferred embodimenteach plunger comprises a cam track cooperating with a common cam shuttlemember comprising followers for each cam track. Preferably such a camshuttle is constrained to move within a void extending perpendicularlyto the plungers. This void could be defined by a separate member or asan integral part of a housing for the syringe.

There are many different patterns of actuation of the two plungers whichthe interlinking could be configured to allow. The skilled person cantherefore select the required pattern depending upon the application forwhich the syringe is to be used. In preferred embodiments where thesyringe is for use in reconstituting and injecting lyophilised drugs,the interlinking is configured to prevent injection of the drug until ithas been reconstituted with diluent.

The two plungers could be made identical in appearance. Preferablyhowever, they are different in appearance—for example one may be largerthan the other or, preferably, they are different colours. This allows auser easily to identify which should be operated at which stage, therebyavoiding frustration or confusion on the part of a user attempting tooperate a plunger which is not intended to be operated at that stage andwhich, therefore, is prevented from doing so.

The two chambers could be maintained isolated from one another so thattheir contents are delivered independently subject to the configurationof the plunger interlink. Preferably however, the syringe is arrangedsuch that the two chambers can be placed selectively in fluidcommunication with one another. This allows, for example, reconstitutionof a lyophilised drug within one of the chambers. In a preferredembodiment a communicating conduit is provided which is movable intofluid communication with one or both of the chambers. Most preferablysuch movement is arranged to breach a seal such as a septum or the likeassociated with one or both of the chambers. For example, thecommunicating conduit may comprise one or two needles for breaching saidseal or seals. If two needles are provided, they may be arranged tobreach the respective seals or the chambers at the same time.Alternatively, they could be arranged to breach the seals in apredetermined order, e.g. by making one longer than the other.

The communicating conduit preferably comprises a tortuous or complexfluid path such that liquid forced therethrough under ordinary manualpressure on one of the plungers is caused to exit the conduitsubstantially without jetting. Provision of a tortuous path giving ahigh pressure drop and low fluid exit speed is especially advantageousin the reconstitution of some lyophilised drugs which can be harmed iffoaming or shearing occurs.

In particularly preferred embodiments the communicating conduit isprovided on a separate support member which is preferably slidabletowards or away from the chambers.

By providing the communicating conduit on a separate support member, thetransient pathway for the substances can be separated from the part ofthe apparatus required to provide storage. This allows, in a preferredembodiment, the superior inertness and barrier properties of glass to beused for the storage section whereas the transient section, which isseparated from the storage section during storage and thus is notsubject to the same stringent inertness and barrier requirements, can bemade from plastics. This substantially facilitates its manufacture andeasily allows the tortuous path mentioned above to be provided. It alsoallows, if suited to the particular application, needles to beintegrally moulded at the ends of the conduit for breaching seals on thechambers. Alternatively separate e.g. steel needles could be attached tothe ends of the conduit for this purpose. Either way, the support membergives another advantage that the user can breach the seals withouthaving to come into contact with a needle since the needles caneffectively be embedded within the structure of the syringe.

Furthermore, by providing a separate sliding support memberincorporating the communicating conduit, fluidly joining the twopreviously separated chambers is easily achieved whilst allowing the twochambers to be fabricated, filled and, where appropriate, sterilisedseparately from one another. An example of why this is advantageous isgiven by the case of an embodiment in which the two chambers arepre-filled with lyophilised drug and diluent respectively. The diluentchamber and peripheral parts of the device must, in general, besterilised. However, the sterilisation process can often damagelyophilised drugs. In accordance with the arrangement described abovehowever, the two chambers may be prepared independently of one anotherand mounted together only in a final step. This facilitates productionof such devices.

In fact it will be appreciated that the foregoing arrangements are noveland inventive in their own right and thus when viewed from a secondaspect the invention provides a syringe for reconstituting a lyophilisedsubstance comprising a first chamber containing or for containing thelyophilised substance and a second chamber containing or for containinga diluent; the first and second chambers being arranged generallyadjacent one another; the syringe further comprising a communicatingconduit for fluidly connecting the two chambers, said fluid connectionmeans being selectively engageable with the two chambers.

Preferably the conduit is provided on a support member separate from thetwo chambers. Most preferably the support is such as to be slidable soas to bring the conduit into and out of engagement with the chambers. Itis also preferred that the two chambers have respective associatedplungers which are interlinked to prevent activation of one dependingupon the position of the other in accordance with the first aspect ofthe invention. Similarly it is also preferred that the conduit has atortuous configuration as previously described to prevent foaming orshearing of the drug during reconstitution.

Where in the present application the term “plunger” is used, it shouldbe appreciated that the invention is not limited to any particular formof construction and that in fact any suitable means of reducing volumein the chamber and/or expelling the contents therefrom could besubstituted.

A preferred embodiment of the invention will now be described, by way ofexample only, with reference to the accompanying drawings in which:

FIG. 1 is a cross-section through a syringe in accordance with theinvention in its storage position;

FIG. 2 shows the syringe of FIG. 1 with the septums pierced;

FIG. 3 shows the syringe after reconstitution of a drug;

FIG. 4 shows the syringe after purge and injection of the drug; and

FIG. 5 shows the syringe after flushing.

Turning firstly to FIG. 1, there may be seen a cross-section through asyringe in accordance with the present invention. It may be seen thatthe syringe comprises two chambers in the form of glass vials 2,4 eachbeing associated with a respective plunger 6,8. Each plunger 6,8 has asynthetic rubber bung 10,12 attached or over-moulded onto the end of thecorresponding plunger. The upper vial 2 is intended in use to contain alyophilised drug and thus the plunger bung 10 is designed to provide anynecessary barrier properties and/or difference in pressure relative toambient which might pertain to the required storage of the particularlyophilised drug in question.

The lower vial 4 is intended in use to contain a liquid diluent suitablefor reconstituting the lyophilised drug in the upper chamber 2. Thus,the bung 12 on the diluent plunger 8 is capable not only of providing aliquid-tight seal, but also of providing a sufficient barrier againstcontamination of the sterilised diluent. In this embodiment the plungers6,8 for the drug and diluent are coloured red and blue respectively forease of identification but this is by no means essential.

At the opposite end of each vial 2,4, is provided a rubber septum 14,16.As with the rubber bungs 10,12, the rubber septums 14,16 provide therequired barrier properties for the intended shelf life of the materialsin the syringe. The two vials 2,4, are held in a two-part clam shellouter casing moulding 18 which also protects them from damage. The outercasing 18 incorporates two finger rests 20 which, as is conventionallyknown, allow a user to apply thumb pressure to the ends of the plungers6,8.

The front end 18 a of the outer moulding defines a pair of apertures22,24 in alignment with the two respective septums 14,16 to provideaccess to them. The housing front end 18 a is covered by a plasticsfront end moulding 26 which is mounted so as to be able to slide axiallyrelative to the syringe housing 18. In the storage position shown inFIG. 1 it is offset towards the left—i.e. at the leftmost end of itstravel, when viewed from FIG. 1.

The front end moulding 26 has a pair of steel needles 28,30 mountedinside which extend into the apertures 22,24 respectively in the frontface of the syringe housing 18 a. In an alternative embodiment (notshown) the needles can be integrally moulded from the same plasticsmaterial as the front cap. The two needles 28,30 are fluidly connectedat their other ends by a conduit in the form of a narrow bore 32.Although not visible in the Figure, the narrow bore 32 has a tortuousconfiguration.

Also in fluid communication with the narrow bore 32 is the central boreof a nozzle 34 at the front end of the front end moulding 26. The nozzle34 will in use be connected to an administration set such as a line set,cannula or hypodermic needle and thus defines the exit path 36 from thesyringe. The nozzle 34 is of standard configuration in order toco-operate with commonly available administration sets. A nozzle cap 36is provided over the nozzle 34 to maintain sterility of the syringe.

Attached to the rear end of the syringe housing 18 is another plasticsmoulding 38, although this could equally be integrally formed with thehousing. The rear moulding 38 defines a void in which is provided a camguiding shuttle 40 which is moveable in within the rear moulding 38 in adirection perpendicular to the plungers 6,8. The shuttle 40 has a pairof integrally moulded cam followers in the form of pins (not visible)which engage respectively in grooves defining cam tracks 42,44 in theshafts of the two plungers 6,8.

It will be seen that in FIG. 1, the shuttle 40 is in its upper positionsince the two followers are at the leftmost ends of the cam tracks42,44. It should further be noted that although the upper cam followeris not prevented from moving down (i.e. towards the main axis of thesyringe) by its cam track 42, it is prevented from doing so by virtue ofbeing integrally formed with the shuttle 40 and therefore the lower camfollower which is prevented from moving in the aforementioned directionby the lower cam track 44. The result of this is that the plunger 6cannot be depressed the user is unable to attempt to expel thelyophilised drug from the vial 2. Moreover, by preventing movement ofthe drug vial plunger 6, a vacuum may be maintained in the drug vial 2which may be important for certain drugs.

During fabrication of the syringe shown in FIG. 1, the two clam shellsof the front end moulding 26 and the needles 28 are assembled togetherby e.g. ultrasonic welding. The nozzle cap 36 is then added to thisassembly. The front end assembly is then assembled onto one clam shellhalf of the syringe outer housing 18 along with the rear end moulding 38and the shuttle 40.

The lower glass vial 4 and plunger 8 are fabricated and assembled andthen filled with a suitable diluent before the rubber septum 16 isfitted. The diluent vial assembly is then mounted into the bottom halfof the main syringe housing 18 to which the front and rear mouldings 26,38 were attached. The whole assembly is then passed through a terminalsterilisation process, known per se.

In a separate part of the fabrication plant, the upper glass vial 2(with plunger 6) is filled with the desired liquid drug and then passedthrough the stages, well known per se in the art, necessary tolyophilise the drug and fit the rubber septum 14.

The drug vial assembly 2,6,14 is assembled into the lower half of thesyringe housing 18 and the upper half of the housing 18 added andsecured to complete the assembly. Thus the diluent vial 4 and the restof the syringe may be sterilised without harming the delicatelyophilised drug which may be prepared in its vial 2 in the normal way.This makes assembly of the syringe straightforward.

It will be appreciated by those skilled in the art that the syringe asshown in FIG. 1 may be stored for a long period of time since thelyophilised drug and the diluent are completely sealed within the twovials 2,4 respectively. Moreover, lyophilisation of the drug ensures itslong term stability. Although the position of the shuttle 40 is notpreventing depression of the diluent plunger 44, in practice suchdepression is prevented by hydraulic resistance of the diluent in thevial 4 since, as mentioned above, the vial is completely sealed.

When it is desired to use the drug by injecting it, the lyophilised drugmust first be reconstituted. The first step in achieving this is shownin FIG. 2. As will be seen from a consideration of FIGS. 1 and 2, inFIG. 2 the front end moulding 26 has been slid onto the front end of thesyringe housing 18 a. This causes the needles 28,30 to pass through theapertures 22,24 in the front of the housing 18 a and to pierce theseptums 14,16. A fluid path between the two vials 2,4 is thereforeprovided via the two needles 28,30 and the narrow bore 32. It will benoted that the cap 36 is retained at this stage in order to ensure thatthe fluid paths 28-34 and the two vials 2,4 are maintained sterile andto ensure that the sole fluid path opened is between the two vials.

Since, in the described embodiment, the lyophilised drug is stored undervacuum in the drug vial 2, when the fluid path is opened as shown inFIG. 2, diluent from the diluent vial 4 will automatically be drawnthrough the narrow bore 32 into the drug vial 2. The reduction inpressure in the diluent vial 4 causes the diluent plunger 8 to moveforwards as may be seen in FIG. 3. Depending upon the degree of vacuumin the drug vial 2, it may be necessary to apply some manual pressure tothe plunger 8 to reach the position shown in FIG. 3. In an alternativeembodiment (not shown) the drug is not stored under pressure and theconfiguration of the cam tracks 42,44 is different in order to allow thesyringe to be stored with the drug plunger partially depressed and ableto move out of the drug vial to accommodate diluent being injected in.

The tortuous narrow bore 32 ensures a high pressure drop across it. Thismeans that under normal manual pressure on the diluent plunger 8,diluent will exit into the drug vial 2 at a dribble—i.e. such a lowliquid velocity that jetting does not occur and potentially harmfulfoaming or shearing are avoided. Mixing of the diluent and thelyophilised drug in the drug vial 2 effects reconstitution of the drugready for use.

It may further be seen from FIG. 3 that the forward movement of thediluent plunger 8 and the downwardly curving shape of the correspondingpart of its cam track 44 causes the shuttle 40 to move from its originalupper position to the lower position. The upwardly kinked shape of thecam track 44 at this point prevents any further forward movement of thediluent plunger 8. A proportion of the diluent will therefore remain inthe diluent vial 4.

It will further be appreciated that since in FIG. 3 the shuttle 40 hasmoved downwards, this will move the cam follower in the cam track 42 ofthe drug plunger 6 thereby enabling it to be depressed when required.However, this will not be possible until the correct quantity of diluenthas been dispersed.

Once reconstitution of the drug has taken place, the cap 36 on thenozzle 34 may be removed and the nozzle 34 attached to a cannula orbutterfly introducer set. The drug plunger 6 is then actuated a shortway to purge the system of air as will be well known to the user. Theuser will then typically insert the hypodermic needle into the patient(which could of course be the user themself), carrying out a vein checkto ensure that the needle is correctly inserted or not in the bloodstream as appropriate. The user may then depress the drug plunger 6fully in order to inject the reconstituted drug into the patient. Duringthis part of the operation, the syringe is used exactly as aconventional syringe would be.

The skilled person will appreciate that although the fluid path betweenthe vials 2,4 via the narrow bore 32 remains open during the injectionprocedure, in practice the difference in pressure between the narrowbore 32 and the exit path through the nozzle 34 will ensure thatsubstantially none of the drug is diverted into the narrow bore 32 orthe diluent vial 4. If necessary, this can be further ensured byproviding the diluent bung 12 with barbed-like projections in order toincrease its resistance to moving back along the vial 4.

Turning now to the shuttle 40, it will be seen that after full actuationof the drug plunger 6, the upward curve at the end of its cam track 42causes the shuttle 40 again to move to its upper position. This permitsfurther actuation of the diluent plunger 8 as may be appreciated byconsidering the shape of its cam track 44.

The final step in the procedure is shown in FIG. 5. In this Figure, itmay be seen that the diluent plunger 6 has also been fully actuated asis permitted by the upward position of the shuttle 40. This flushes allthe internal fluid paths 30,32,34 of any remaining drug using theremainder of the diluent. The only part of the system which will not beflushed is the drug needle 28, but it will be appreciated by thoseskilled in the art that the volume of the needle 28 is extremely low andat least an order of magnitude less than the volume of a standardsubcutaneous cannula. The difference is even more pronounced whencompared with a butterfly introducer. Thus, it may be ensured that thepatient receives substantially all of the intended dose.

It will be seen from the foregoing description that at least a preferredembodiment of the invention provides a two-part syringe which can beused to store and subsequently reconstitute a lyophilised drug andthereafter inject it into a patient in an entirely conventional mannerwithout the user ever having to come into contact either with the drugor the diluent, or indeed without having manually to pierce the septumswith a needle.

More importantly, however, it will also be seen that the interlinking ofthe two plungers by the shuttle and respective cam tracks ensures thatonly the correct plunger may be actuated at the correct time. This makesadministration of the drug by non-medical staff or self-administrationby patients a greater possibility.

It will be appreciated by those skilled in the art that the embodimentdescribed above is just one example of the application of the principlesof the present invention and that many variations and modifications arepossible within the scope of the invention. For example, the inventionis not limited to the reconstitution of lyophilised drugs and indeedembodiments of the invention may find many different applications whereit is desired to ensure the correct sequence of actuation of a pair ofsyringe plungers.

1. A two-part syringe comprising two chambers, each chamber having anassociated plunger operable to eject fluid therefrom, said plungersbeing interlinked so as selectively to prevent movement of one of saidplungers in its respective chamber dependent upon the position of theother plunger.
 2. A syringe as claimed in claim 1 comprising a cam meansis associated with the plungers.
 3. A syringe as claimed in claim 2wherein each plunger comprises a cam track cooperating with a common camshuttle member comprising followers for each cam track.
 4. A syringe asclaimed in claim 3 wherein said cam shuttle is constrained to movewithin a void extending perpendicularly to the plungers.
 5. A syringe asclaimed in claim 1 for use in reconstituting and injecting a lyophiliseddrug, wherein said interlinking is configured to prevent injection ofthe drug until it has been reconstituted with diluent.
 6. A syringe asclaimed in claim 1 wherein the plungers are different in appearance. 7.A syringe as claimed in claim 1 arranged such that the two chambers canbe placed selectively in fluid communication with one another.
 8. Asyringe as claimed in claim 7 comprising a communicating conduit whichis movable into fluid communication with one or both of the chambers. 9.A syringe as claimed in claim 8 wherein said movement is arranged tobreach a seal such as a septum or the like associated with one or bothof the chambers.
 10. A syringe as claimed in claim 9 wherein thecommunicating conduit comprises one or two needles for breaching saidseal or seals.
 11. A syringe as claimed in claim 8 wherein saidcommunicating conduit comprises a tortuous or complex fluid path suchthat liquid forced therethrough under ordinary manual pressure on one ofthe plungers is caused to exit the conduit substantially withoutjetting.
 12. A syringe as claimed in claim 8 wherein said communicatingconduit is provided on a separate support member which is preferablyslidable towards or away from the chambers.
 13. A syringe as claimed inclaim 12 wherein said separate support member is made from plastics. 14.A syringe for reconstituting a lyophilised substance comprising a firstchamber containing or for containing the lyophilised substance and asecond chamber containing or for containing a diluent; the first andsecond chambers being arranged generally adjacent one another; thesyringe further comprising a communicating conduit for fluidlyconnecting the two chambers, said fluid connection means beingselectively engageable with the two chambers.
 15. A syringe as claimedin claim 14 wherein said conduit is provided on a support memberseparate from the two chambers.
 16. A syringe as claimed in claim 15wherein said support member is such as to be slidable so as to bring theconduit into and out of engagement with the chambers.
 17. A syringe asclaimed in claim 14 wherein the two chambers have respective associatedplungers which are interlinked to prevent activation of one dependingupon the position of the other.
 18. A syringe as claimed in claim 14wherein the conduit has a tortuous configuration.